A number of publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference in this application as though set forth herein in full.
Human herpes virus-8 (HHV-8) is a recently identified virus that has been associated with Kaposi's sarcoma (KS) and possibly with a type of cancer called body cavity lymphoma (a tumor that arises from the lymph tissue) (1). HHV-8, also known as Kaposi's sarcoma-associated herpes virus (KSHV), is an important pathogen capable of causing disease that affects all age groups worldwide (2). KS is an unusual skin tumor that is seen primarily in HIV-infected men. HHV-8 has also been isolated in the semen of HIV infected individuals. Because of these factors, it is believed that HHV-8 may cause a sexually transmitted infection.
From the beginning of the AIDS epidemic, it was suspected that there might be another infectious agent besides HIV that causes KS. In the 1980's, around 30-40% of homosexual men with AIDS developed KS at some point in their illness. In contrast, KS was a rare occurrence in women or hemophiliacs with HIV. This suggested that there was an additional factor among gay and bisexual men that increased their risk of developing KS. In 1994, HHV-8, which was previously unknown, was identified by researchers in KS biopsies (3). This virus belongs to the important family of human herpesviruses that includes varicella-zoster (chickenpox/shingles), epstein-barr virus (mononucleosis), and herpes simplex 1 and 2 (oral and genital herpes). After identification of HHV-8, researchers have been able to identify this virus in virtually all types of KS tumors, including those seen before the AIDS epidemic.
The complete HHV-8 genome sequence has sequence similarities to the sequences of other gammaherpesviruses, including herpesvirus saimiri (HVS), murine gammaherpesvirus 68 (MHV68) and Epstein-Barr Virus (HHV-4). The ˜165 kb genome contains over 80 open reading frames arranged in a long unique region flanked by multiple 801 bp terminal repeat units of high G+C content. The long unique region contains blocks of conserved genes found in most herpesviruses, interspersed with blocks of non-homologous genes that are specific for HHV-8 and related viruses.
The pathogenic mechanism by which HHV-8 induces tumorigenicity is presently unknown. However, HHV-8 encodes a G-protein coupled receptor (GPCR) that acts as an oncogene, the expression of which causes malignant transformation of rodent fibroblast cells, and produces tumors in nude mice. Transgenic mice expressing the HHV-8-GPCR develop highly vascular endothelial tumors (4-6). Such tumorigenicity relates to the ability of the HHV-8-GPCR to constitutively activate the extracellular signal-regulated kinase (ERK) signal-transduction cascade (7),(8). One of the main activators of the ERK cascade is the Ras-Raf-MEK1/2-ERK signaling axis (9). Further, in some cases, GPCRs are known to signal through Ras (10-12). Inasmuch as a number of viruses utilize this signaling axis to establish infection, agents, which disrupt this pathway should prove efficacious against viruses, which include, for example, Epstein Bar Virus and Hepatitis B virus.
Clearly a need exists for compositions and methods useful for treating viral infections, including KSHV. The present application provides such compositions and methods.